Opioids are a class of drugs that include both natural and synthetic substances. The natural opioids (referred to as opiates) include opium and morphine. Heroin, the most abused opioid, is synthesized from opium. Other synthetic opioids, commonly prescribed for pain, as cough suppressants, or as anti-diarrhea agents, includes, codeine, oxycodone (OXYCONTIN®), meperidine (DEMEROL®), fentanyl (SUBLIMAZE®), hydromorphone (DILAUDID®), methadone and propoxyphene (DARVON®). Heroin is usually injected, either intravenously or subcutaneously, but can also be smoked or used intranasally. Other opioids are either injected or taken orally.
Opioids, whether used in a clinical or non-clinical environment, are highly addictive and can lead to varying degrees opioid toxicity. Some chronic opioid users known as “addicts” continue abusing the opioid despite significant problems caused by or made worse by the use of opioid. Typically, chronic users become physically dependent on the opioid, as evidenced by tolerance and/or withdrawal. Acute users experience opioid intoxication, wherein the user uses a sufficient amount of an opioid to get a “high”. These acute users do not experience typical withdrawal symptoms upon elimination of the opioid, however, may experience overdose symptoms (e.g., opioid-induced coma) when too much of an opioid is taken.
Traditionally there are several forms of opioid detoxification programs targeting users with various degrees of opioid tolerance. Typical treatment regimes allow for complete elimination of the opioid from the user's body and prevent the user from reestablishing a dependence on the opioid. Opioid receptor antagonists are one form of treatment effective at reversing the clinical features of opioid toxicity. Opioid receptor antagonist functions by completely binding to the same receptors as the opioid. The opioid receptor antagonist displaces the opioid while having the added advantage of having no addictive potential because of its inability to activate opioid receptors. This approach has the promising effect of reducing the pharmacodynamic effects (e.g. “high”) of the opioid user at a very rapid rate while allowing for the opioid agonist to be eliminated from the body. However, the very rapid removal rate of the opioid may result in exaggerated withdrawal symptoms for addicts with tolerance to the opioid.
An opioid antagonist, naloxone (NARCAN®), is often administered to reverse the effects of opioid intoxication or overdose. The drawback to this treatment is that the duration of action of some opioids may exceed that of a single naloxone administration. The pharmacodynamic actions of naloxone last for a briefer period than all but the most short acting opioids. Clarke, S F J et al., Emergency Medicine Journal, 2005 (22) 612-616. Clarke notes that, “although the elimination half life of naloxone is similar to that of morphine (60-90 minutes) it is redistributed away from the brain more rapidly. Consequently, the patients may become renarcotised and suffer harm if they self discharge from medical care early. Clinicians are clearly walking a tightrope between precipitating AWS (acute withdrawal syndrome) and avoiding renarcotisation.” Clarke at 612. Therefore, continued surveillance is needed which is often achieved by hospitalization. Furthermore, in patients with renal and hepatic failures require large doses of naloxone over long periods. Maintaining therapeutically effective naloxone concentration is a challenge. Redfern, N., British Medical Journal, 1983 (287) 751-752. As such, new therapeutics for the treatment of drug overdose/toxicity that are effective for a longer period is needed.